α-Actinin-4 (hereinafter also referred to as ACTN4), which is a member of α-actinin, has a globular actin-binding domain at the N-terminal end and a calcium-binding motif (referred to as an EF-hand domain) at the C-terminal end. Moreover, ACTN4 forms dumbbell-shaped dimer through its central rod domain, and binds and bundles actin filaments with the actin-binding domain at each end (Non-patent Document 1). Mammalian α-actinin has been identified to have four isoforms, i.e., actinin-1 to actinin-4, wherein actinin-1 and actinin-4 are non-muscle isoforms, while actinin-2 and actinin-3 are muscle isoforms (Non-patent Documents 1, 2, 3 and 4).
ACTN4 is an actin-binding protein which is involved in actin bundling and promotes cell motility. It has been verified that ACTN4 is concentrated in cellular protrusions which appear to have enhanced cell motility. Further, it is suggested that ACTN4 may provide some positive contribution to cancer invasion (Non-patent Document 2).
In addition, a selective splice variant which skips exon 8 (where genetic mutations are found in families with familial focal glomerulosclerosis) and inserts novel (unknown) exon 8′ is expressed specifically in small cell lung cancer, and its expression is verified only in testis among normal tissues; and hence it is suggested that this selective splice variant may be a cancer-testis antigen (Non-patent Document 5).
On the other hand, lung cancer is classified into two types, i.e., small cell lung cancer (hereinafter referred to as SCLC) and non-small cell lung cancer (hereinafter referred to as non-SCLC) by histological analysis. SCLC accounts for 20% of primary lung cancer and is often found in progressive form associated with multiple organ metastasis due to its high growth speed; and hence SCLC is known for “high malignancy” and “poor prognosis” (Non-patent Document 5).
In therapeutic aspects, SCLC requires different therapies from those for non-SCLC, most cases of which are adenocarcinoma and squamous cell carcinoma. For example, surgical therapies cannot be applied to SCLC even when it is in slightly advanced stage, while chemotherapies are less effective in non-SCLC cases. Because of these features, it has been considered that differentiation between SCLC and non-SCLC in an early stage is important for their appropriate treatment.
Moreover, large cell neuroendocrine carcinoma (hereinafter referred to as LCNEC), which is a subtype of large cell cancer included in non-SCLC, accounts for 3% of primary lung cancer and is known for “poor prognosis,” as in the case of SCLC. LCNEC and SCLC are both high in neuroendocrine character, unlike other types of lung cancer (Non-patent Document 6).
Conventionally, SCLC and LCNEC have been collectively referred to as lung primary high-grade neuroendocrine tumor (HGNT), and, immunostaining utilizing neuroendocrine markers (chromogranin, synaptophysin, neural cell adhesion molecule (NCAM)) has been performed on excised specimens as one of their diagnostic techniques (Non-patent Document 7).
However, the positive rate of these three markers is far from being high, and their high false positive rate has been regarded as a problem. Thus, it is anticipated to develop a novel cancer marker which is highly specific to both small cell lung cancer and large cell neuroendocrine carcinoma and which allows early stage detection.